Highlights from Recent Cancer Literature
Journal: Cancer Research (2018)

Dysregulation of epigenetic regulation is frequently observed in different cancers, therefore targeting of epigenetic regulators is a key area for cancer treatment. Sheng and colleagues reveal that disrupting the activity of LSD1, a histone H3K4 demethylase, in cancer cells enhances intratumoral T-cell recruitment and improves the efficacy of anti-PD1–based immunotherapy. Mechanistically, loss of LSD1 function increases endogenous retroviral elements (ERV) that initiate a double-stranded RNA (dsRNA) stress response, activating interferon, and bolsters the immune response. LSD1 loss increases H3K4me2 at ERVs, enhancing their transcription. LSD1 loss also decreases the stability of the RNA-induced silencing component Argonaute-2 (AGO2), which would otherwise degrade dsRNAs. The authors discovered that AGO2 is stabilized by LSD1 directly via demethylation. Mining The Cancer Genome Atlas database revealed an inverse correlation between LSD1 expression and the degree of T-cell infiltration in many human cancers.Expert Commentary: Targeting LSD1 in cancer enhances ERV-induced dsRNA stress responses that can promote cancer immunotherapy.Sheng W, LaFleur MW, Nguyen TH, Chen S, Chakravarthy A, Conway JR, et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell 2018;174:549–63.Exome sequencing has provided information about mutations in protein-coding regions. Much less is known about structural changes genome wide. Quigley and colleagues defined genomic hallmarks and structural changes that occur in prostate cancer by using integrative deep whole-genome and -transcriptome analysis of 101 prostate cancer metastases. The authors found amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of the patients, correlating with increased levels of AR. Tandem duplication hotspots in lncRNAs near the MYC gene were linked to posttranslational regulation of the MYC protein. Structural variations associated with DNA repair deficiencies, including mutations of CDK12, TP53, and BRCA2.Expert Commentary: These data provide insights into how structural variations affect important regulators in metastatic prostate cancer. This information may be useful for diagnosis, prognosis, and treatment.Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell 2018;174:758–769.e9. doi: 10.1016/j.cell.2018.06.039.To characterize the subclonal architecture of pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG), Vinci and colleagues analyzed 142 pGBM biopsies and multiregional sampling from 14 DIPGs. Histone mutations K27M, G34V, ATRX, and NF1 were consistently clonal. Several actionable mutations were subclonal: 85% of tumors harbored 3-10 subclones. Multiple subclones showed differential responses to PARP inhibition. Subclonal mutations in the H4 methyltransferase KMT5B were present in a small proportion of cells, with some subclones approaching 100%. Strikingly, these subclones had different mutational landscapes, secretory factors, and invasive capacity, suggesting they worked in parallel to drive tumorigenesis.Expert Commentary: The identification of multiple subclones acting in concert suggests that a single resistant population does not drive relapse. Therapies must be tailored towards each population individually.Vinci M, Burford A, Molinari V, Kessler K, Popov S, Clarke M, et al. Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells. Nat Med 2018;24:1204–15.Highly proliferative cancer cells require increased protein synthesis and upregulated ribosomal biogenesis programs, while senescent cells exhibit G1/S cell-cycle arrest with reduced ribosomal biogenesis. Lessard and colleagues demonstrated that oncogene- and stress-induced senescence is associated with accumulation of rRNA precursors and ribosomal proteins resulting from proteasome-dependent degradation of ribosome biogenesis factors. The ribosomal protein S14 (RPS14) accumulates in the nucleus and nucleolus, binding and inhibiting CDK4, leading to activated Rb, cell-cycle arrest, and senescence. This mechanism was independent of p53 but dependent on Rb, suggesting induction of senescence as a therapeutic opportunity in cancers with inactivated p53.Expert Commentary: This study provides mechanical proof of the role of RNA biogenesis in senescence and a rationale for targeting this mechanism to selectively arrest tumor cell proliferation.Lessard F, Igelmann S, Trahan C, Huot G, Saint-Germain E, Mignacca L, et al. Senescence-associated ribosome biogenesis defects contribute to cell cycle arrest through the Rb pathway. Nat Cell Biol 2018;20:789–99.Metastatic outgrowth of disseminated tumor cells (DCC) is the major cause of cancer-related mortality. The perivascular niche at metastatic sites, a nutrient-rich environment, supports survival of DCCs. Er and colleagues show that DCCs can compete with pericytes for cell adhesion molecule L1 (L1CAM)-dependent spreading on capillaries in the perivascular niche. L1CAM activates the mechanotransduction effectors YAP and MRTF by engaging β1-integrin and integrin-linked kinase (ILK). Activation of this signaling axis provides mechanotransduction cues enabling outgrowth of tumor cells in the metastatic niche following extravasation and also after periods of latency.Expert Commentary: The observation that the L1CAM-ILK-YAP signaling axis drives metastatic outgrowth in multiple organs provides potential therapeutic strategies for the treatment of disseminated disease. The ability of tumor cells to hijack normal pericyte processes and signaling pathways has implications for therapy.Er EE, Valiente M, Ganesh K, Zou Y, Agrawal S, Hu J, et al. Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization. Nat Cell Biol 2018;20:966–78.Eph receptor tyrosine kinases (EphR) are expressed by glioblastoma stem cells (GSC), linked to therapy-resistance. Qazi and colleagues utilized an EphR profiler to simultaneously assess protein levels of all EphRs in cells comprising primary and recurrent glioblastoma (rGBM). Coexpression of EphA2 and EphA3 identified a highly tumorigenic cell population in rGBM enriched in markers of GSCs. Knockdown of EphA2 and EphA3 in combination blocked enhanced survival in vivo. Treatment of rGBM with a bispecific antibody against EphA2/A3 reduced tumorigenic potential of xenografted rGBM in vivo via downregulation of Akt and Erk and increased differentiation.Expert Commentary: Comprehensive profiling of the entire EphR family in human rGBM and functional characterization of GSC populations generated a novel, empiric poly-targeted therapy that offers promise to patients with rGBM.Qazi MA, Vora P, Venugopal C, Adams J, Singh M, Hu A, et al. Cotargeting ephrin receptor tyrosine kinases A2 and A3 in cancer stem cells reduces growth of recurrent glioblastoma. Cancer Res 2018;78:5023–37.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.